PROJECT SUMMARY Relapse to drug abuse is the single greatest challenge in addiction treatment. Relapse can occur even after prolonged abstinence and is often preceded by robust drug craving precipitated by exposure to drug-paired stimuli and environments. Aerobic exercise is a novel and promising behavioral treatment for drug addiction and relapse. However, the precise mechanism of its therapeutic effects is unknown. The long-term goal of this project is to characterize the striatal network dynamics that mediate the effects of exercise on addiction and relapse. The current aims of this proposal are to examine the impact of chronic wheel running on rapid subsecond dopamine release dynamics and dopamine terminal function as well as on the longitudinal development of phasic dopamine signals that promote cocaine-seeking behavior and on the recruitment of cell- type specific neural processing of cocaine seeking and cocaine-paired cues. It is hypothesized that chronic wheel running will (1) attenuate cocaine-evoked subsecond dopamine release in the striatum, (2) decrease striatal phasic dopaminergic signals accompanying cocaine-paired cues and cocaine seeking, and (3) attenuate D1-MSN and potentiate D2-MSN encoding of cocaine-paired cues and cocaine seeking. These experiments will employ a sophisticated mouse model of cocaine relapse, state-of-the-art in vivo fast-scan cyclic voltammetry recordings, in vivo multiple single-unit electrophysiological recordings, and chemogenetic and optogenetic technologies to examine these questions in behaving animals. The proposed experiments aim to increase our understanding of the neurobiological substrates that mediate drug craving and relapse and identify the neurochemical and neurophysiological mechanisms of the beneficial effects of exercise.